SPRINT Proves that Lower Is Better for Nondiabetic High-Risk Patients, but at a Price

SPRINT was a well designed and executed randomized clinical trial funded by the National Institutes of Health (NIH) in which 9,361 hypertensive patients at high risk of cardiovascular disease with blood pressure (BP) above 130 mm H g and below 180 mm H g, were randomly assigned to be treated to a goal systolic BP (SBP) of less than 140 vs. less than 120 mm Hg. The trial recruited hypertensive individuals in the United States who were older than 50 years of age and had never had a stroke and were not diabetic, but were either older than 75 years of age (28% of subjects), had chronic kidney disease with estimated glomerular filtration rate (eGFR) 20 m l/min/1.73 m 2 of body surface (28% of subjects), or had clinical or subclinical cardiovascular disease or a Framingham score indicating 10-year risk of >15% of cardiovascular disease. By 1-year post-randomization, the trial achieved SBPs of 121.4 mm H g in the intensive treatment group and 136.2 mm H g in the standard treatment group, a difference that was maintained throughout the trial. SPRINT was stopped early after a median follow-up of 3.26 years because of a 25% relative risk reduction in the intensive treatment group of the primary endpoint (myocardial infarction or other coronary syndromes, stroke, heart failure, or death from cardiovascular causes) and 27% in all-cause mortality. In order to achieve these results, patients in the intensive therapy group took a mean of approximately 3 vs. 2 antihypertensive drugs in the standard therapy group. About 3,000 patients in each group completed 3 years of the trial, a little more than 1,000 completed 4 and slightly less than 300 in each group completed 5 years of the trial. The beneficial results were found across all prespecified groups. However, it is noteworthy that individuals older than 75 years of age appeared to benefit more than younger subjects. Is it possible that these older individuals were “survivors,” who although at high cardiovascular risk, were able to benefit more than the more “mixed” younger group? As well, those subjects who entered the trial with SBP of <132 mm H g also benefited more than those who entered the trial with higher SBP, both in terms of relative and absolute risk reduction. The protocol required that individuals assigned to the standard therapy group who entered with lower BP than goal have their antihypertensive medication down-titrated. 2 In contrast, those assigned to the intensive therapy group would be up-titrated. No specific drug algorithm was used and the broad range of antihypertensive drugs utilized were provided to participants free of charge. Since among secondary endpoints 2 were highly significant in favor of the intensive therapy group, heart failure, and death from cardiovascular disease, as well as all-cause mortality, is it possible that in a high-risk population down-titration of medication, perhaps renin–angiotensin inhibitors, vs. use of a high dose of these in the intensive therapy group, progressively uncovered latent heart failure contributing to the results observed? The rise in BP after down-titration may also have contributed to the higher event rates for these conditions. Importantly, serious adverse effects deemed related to treatment were twice as frequent in the intensive therapy group than in the standard therapy group, and although not trivial and some